-
The Journal of Clinical Investigation Aug 1977The urines of two unrelated children with inherited deficiencies of purine nucleoside phosphorylase have been found to contain significant quantities of orotic acid in...
The urines of two unrelated children with inherited deficiencies of purine nucleoside phosphorylase have been found to contain significant quantities of orotic acid in addition to the previously reported purine nucleosides. The data are consistent with some cell types of these immunodeficient patients being deplete of pyrophosphoribosylphosphate, a precursor of both purine, and pyrimidine nucleosides. It is suggested that the pyrophosphoribosyl-phosphate-depleted cells may be some component of the thymus-dependent immune system.
Topics: Child; Chromatography, High Pressure Liquid; Humans; Orotic Acid; Pentosyltransferases; Purine-Nucleoside Phosphorylase
PubMed: 406278
DOI: 10.1172/JCI108800 -
The Tohoku Journal of Experimental... Jan 2000A screening system for pyrimidine metabolism disorders by measurement with high-performance liquid chromatography using dried filter-paper urine samples is presented....
A screening system for pyrimidine metabolism disorders by measurement with high-performance liquid chromatography using dried filter-paper urine samples is presented. This system permits the simultaneous determination of dihydrouracil, uracil, orotic acid and pseudouridine. The coefficient of variations for the four compounds on the filter-paper urine samples were 0.010 approximately 0.069 and the recoveries were 98.5 approximately 107.1%. The detection limits of the four compounds were 2 approximately 20 micromol/liter. The correlation between the filter-paper urine samples and liquid urine samples was excellent (0.938-0.988). We supeculated that this method could be used to detect pyrimidine metabolism disorders, such as dihydropyrimidinuria, dihydropyrimidine dehydrogenase deficiency and hereditary orotic aciduria. As a pilot study, we have analyzed dried filter-paper urine samples from 34, 200 healthy Japanese, and found three cases of dihydropyrimidinuria without clinical symptoms.
Topics: Drug Stability; Humans; Infant; Infant, Newborn; Mass Screening; Metabolic Diseases; Pilot Projects; Pyrimidines; Reference Values; Sensitivity and Specificity
PubMed: 10750737
DOI: 10.1620/tjem.190.23 -
The Journal of Veterinary Medical... Mar 2007A 4-months-old calf of Japanese black cattle was diagnosed with orotic aciduria by gas-chromatography/mass-spectrometry (GC/MS). Until now orotic aciduria had not been...
A 4-months-old calf of Japanese black cattle was diagnosed with orotic aciduria by gas-chromatography/mass-spectrometry (GC/MS). Until now orotic aciduria had not been reported in Japanese black cattle. The animal showed repeated diarrhea. The hematocrit was low, and microcytes and acanthocytes were observed in blood smears. The calf had lower serum total protein concentrations with a higher blood ammonia concentration. Needle-shaped crystals of orotic acid were observed in urinary sediments. Sequence homologous analysis with cattle uridine monophosphate synthase DNA indicated silent mutation in the affected calf.
Topics: Animals; Cattle; Cattle Diseases; DNA Mutational Analysis; Deficiency Diseases; Fatal Outcome; Gas Chromatography-Mass Spectrometry; Male; Multienzyme Complexes; Orotate Phosphoribosyltransferase; Orotic Acid; Orotidine-5'-Phosphate Decarboxylase; Pedigree
PubMed: 17409652
DOI: 10.1292/jvms.69.313 -
The Journal of Clinical Investigation Apr 1961
PubMed: 16695858
DOI: 10.1172/JCI104298 -
BMC Pediatrics Dec 2002Hyperammonemia, hypoglycemia, hepatopathy, and ventricular tachycardia are common presenting features of carnitine-acylcarnitine translocase deficiency (Mendelian...
BACKGROUND
Hyperammonemia, hypoglycemia, hepatopathy, and ventricular tachycardia are common presenting features of carnitine-acylcarnitine translocase deficiency (Mendelian Inheritance in Man database: *212138), a mitochondrial fatty acid oxidation disorder with a lethal prognosis. These features have not been identified as the presenting features of mitochondrial cytopathy in the neonatal period.
CASE PRESENTATION
We describe an atypical presentation of mitochondrial cytopathy in a 2 day-old neonate. She presented with a Reye-like syndrome episode, premature ventricular contractions and ventricular tachycardia. Initial laboratory evaluation exhibited a large amount of 3-methylglutaconic acid on urine organic acid analysis, mild orotic aciduria and a nonspecific abnormal acylcarnitine profile. The evaluation for carnitine-acylcarnitine translocase deficiency and other fatty acid oxidation disorders was negative. The patient later developed a hypertrophic cardiomyopathy and continued to be affected by recurrent Reye-like syndrome episodes triggered by infections. A muscle biopsy exhibited signs of a mitochondrial cytopathy. During the course of her disease, her Reye-like syndrome episodes have subsided; however, cardiomyopathy has persisted along with fatigue and exercise intolerance.
CONCLUSIONS
This case illustrates that, in the neonatal period, hyperammonemia and ventricular tachycardia may be the presenting features of a lethal carnitine-acylcarnitine translocase deficiency or of a mitochondrial cytopathy, associated with a milder clinical course. This association broadens the spectrum of presenting phenotypes observed in patients with disturbed mitochondrial energy metabolism. Also, the presence of 3-methylglutaconic aciduria suggests mitochondrial dysfunction and mild orotic aciduria could potentially be used as a marker of mitochondrial disease.
Topics: Biomarkers; Carnitine; DNA, Mitochondrial; Female; Glutarates; Humans; Infant, Newborn; Mitochondrial Myopathies; Mutation; Orotic Acid; Reye Syndrome; Tachycardia, Ventricular
PubMed: 12507404
DOI: 10.1186/1471-2431-2-12 -
The Journal of Clinical Investigation Feb 1996We have achieved significant improvement of ornithine transcarbamylase deficiency (OTCD) in a mouse model through adenoviral-mediated gene transfer of the human...
We have achieved significant improvement of ornithine transcarbamylase deficiency (OTCD) in a mouse model through adenoviral-mediated gene transfer of the human ornithine transcarbamylase cDNA. Substantial reduction in orotic aciduria was observed within 24 h of treatment. Metabolic correction was later associated with phenotypic correction and moderate increase in enzymatic activity. In an effort to identify the level of gene expression required to achieve wild-type levels of enzyme activity we uncovered a dominant negative effect of the endogenous mutant protein on the activity of the delivered recombinant wild-type protein. This phenomenon is relevant to homomultimeric protein defects such as OTCD, represent a challenging category of disorders for gene therapy. Thus, although our findings indicate that adenoviral-mediated gene transfer may have potential as a short-term treatment for OTCD in humans and may be effective especially during catabolic crisis, the observations in this study suggest that careful patient selection based on mutation class may be essential for initial OTCD gene therapy trials, and perhaps, for other homomultimeric enzyme deficiencies being considered as gene therapy targets.
Topics: Adenoviridae; Animals; Disease Models, Animal; Gene Expression; Genetic Therapy; Genetic Vectors; Humans; Intestines; Liver; Metabolism, Inborn Errors; Mice; Mice, Mutant Strains; Ornithine Carbamoyltransferase; Ornithine Carbamoyltransferase Deficiency Disease; Orotic Acid; Patient Selection; Treatment Outcome
PubMed: 8609240
DOI: 10.1172/JCI118482 -
Proceedings of the National Academy of... Apr 1969A hybrid cell line of clonal origin has been obtained by cocultivation of two biochemically marked human cell strains. One parental line is diploid and derived from a...
A hybrid cell line of clonal origin has been obtained by cocultivation of two biochemically marked human cell strains. One parental line is diploid and derived from a male infant with orotic aciduria, a rare autosomal recessive disease. This line has deficient activity for the final two enzymes in the biosynthetic pathway leading to uridylic acid and possesses the B electrophoretic type of glucose-6-phosphate dehydrogenase. The other parental line (D98/AH-2) is heteroploid, is resistant to 8-azahypoxanthine, and has deficient inosinic acid pyrophosphorylase activity. It displays the A(+) variant of glucose-6-phosphate dehydrogenase. The A(+) and B types of this dehydrogenase are known to be determined by allelic, sex-linked, Mendelian genes. The cloned hybrid cells exhibit genetic traits of both parents: (1) Their modal chromosome number is approximately the sum of those of the two parental lines; (2) they have levels of activity for both enzymes affected by the gene for orotic aciduria which are intermediate between those of the two parental lines; (3) they have higher activity than the D98/AH parent for inosinic acid pyrophosphorylase; (4) they have both A(+) and B isozyme bands of glucose-6-phosphate dehydrogenase. These hybrid cells represent the first known example of a cloned line of mammalian origin in which two X-linked allelic genes function.
Topics: Carboxy-Lyases; Cell Line; Culture Media; Culture Techniques; Cytogenetics; Electrophoresis; Gels; Glucosyltransferases; Humans; Hybridization, Genetic; Hypoxanthines; Karyotyping; Methods; Molecular Biology; Orotic Acid; Starch
PubMed: 5256409
DOI: 10.1073/pnas.62.4.1085 -
Clinical Chemistry Nov 2004The concentrations of the pyrimidine "de novo" metabolites and their degradation products in urine are useful indicators for the diagnosis of an inborn error of the...
BACKGROUND
The concentrations of the pyrimidine "de novo" metabolites and their degradation products in urine are useful indicators for the diagnosis of an inborn error of the pyrimidine de novo pathway or a urea-cycle defect. Until now, no procedure was available that allowed the analysis of all of these metabolites in a single analytical run. We describe a rapid, specific method to measure these metabolites by HPLC-tandem mass spectrometry.
METHODS
Urine or urine-soaked filter-paper strips were used to measure N-carbamyl-aspartate, dihydroorotate, orotate, orotidine, uridine, and uracil. Reversed-phase HPLC was combined with electrospray ionization tandem mass spectrometry, and detection was performed by multiple-reaction monitoring. Stable-isotope-labeled reference compounds were used as internal standards.
RESULTS
All pyrimidine de novo metabolites and their degradation products were measured within a single analytical run of 14 min with lower limits of detection of 0.4-3 micromol/L. The intra- and interassay variation for urine with added compounds was 1.2-5% for urines and 2-9% for filter-paper extracts of the urines. Recoveries of the added metabolites were 97-106% for urine samples and 97-115% for filter-paper extracts of the urines. Analysis of urine samples from patients with a urea-cycle defect or pyrimidine degradation defect showed an aberrant metabolic profile when compared with controls.
CONCLUSION
HPLC with electrospray ionization tandem mass spectrometry allows rapid testing for disorders affecting the pyrimidine de novo pathway. The use of filter-paper strips could facilitate collection, transport, and storage of urine samples.
Topics: Argininosuccinic Aciduria; Child; Child, Preschool; Chromatography, High Pressure Liquid; Dihydrouracil Dehydrogenase (NADP); Humans; Infant; Infant, Newborn; Ornithine Carbamoyltransferase Deficiency Disease; Paper; Pyrimidines; Reference Values; Sensitivity and Specificity; Specimen Handling; Spectrometry, Mass, Electrospray Ionization
PubMed: 15375016
DOI: 10.1373/clinchem.2004.038869